OVERVIEW MDU: Innovative Approaches for Cocaine Pharmacotherapy This is a competitive renewal of a NIDA-funded P50 Research Center that serves as one of NIDA's Medication Development Units (MDU). Our MDU complements Penn's longstanding research program to develop effective treatments for drug addiction. The integration of our MDU within the umbrella of the Penn/VA Center for the Studies of Addiction (CSA) allows us to conduct a substantial amount of specialty research (e.g., focused on cocaine addiction; pharmacotherapy treatments), independent of other funded programs that are more generally focused on opiates and other types of addiction, or, on non-medication research programs. Yet, the MDU benefits greatly from Center integration because it permits access to infrastructure resources not provided by this P50 Center. The theme of our MDU is testing innovative medication combinations for managing "hard-to-treat" cocaine/alcohol dependent patients. Previously our P50 focused primarily on several types of severe cocaine dependence, but patients with the combined dependence have become most common. This group responds poorly to existing treatments and has received little research attention in the past. The MDU CORE coordinates the components, conducts an active pilot program, provides a structure for mentoring young, career investigators who want to specialize in cocaine research, and has priority access to important on-site resources: 1) General Clinical Research Center (GCRC) - an inpatient facility for conducting safety trials; 2) Center bio-statistician; 3) web-based Data Management Unit, and 4) a specialty drug screen lab. The pilot program, a critical part of any center, will emphasize novel medication discovery using animal models and brain imaging to test medications that are candidates for future clinical trials. The proposed components in this application reflect developing prototypes, which contain descriptions of specific projects to be done over the next 5 years. Basically, projects are arranged to allow for novel medications to be systematically studied in human subjects (normal controls and patients} from safety through efficacy. Component 1 evaluates a promising novel compound, topirimate, in a randomized, placebo-controlled trial. Component 2 describes a series of safety/tolerability monitoring studies that are necessary prior to combining medications in a large clinical trial. Component 3 operationalizes a large controlled trial to evaluate the efficacy of combination medications in cocaine-alcohol dependent patients. Component 4 describes a model that identifies potential individual genetic predictors to medication response.